Summary

Mammalian cells exposed to N-methyl-N′-nitro-N-nitrosoguanidine show an immediate inhibition of DNA, RNA, and protein synthesis, as judged by radioactive precursor incorporation. DNA synthesis as determined by thymidine-3H uptake is most sensitive in this respect. The inhibition is not due to impaired uptake or phosphorylation of precursor. Studies at the enzyme level show DNA polymerase to be inhibited by N-methyl-N′-nitro-N-nitrosoguanidine in a dose-dependent manner. Experiments with exogenous thiols indicate that thiol groups of DNA polymerase may be targets for reaction with the guanidino radical resulting from N-methyl-N′-nitro-N-nitrosoguanidine decomposition. Further studies suggest that these and other groups possibly involved in substrate binding may be altered and that enzyme kinetics favor a mixed mode of enzyme inhibition.